The Email That Started It All

The Canadian-born chemist retired in December 2012, assuming he’d finally have a chance to focus on decks and houses. And for a year, that’s what happened.

He painted the windows he’d neglected during his tenure as a scientist; fixed up his deck; volunteered for Habitat for Humanity; got his blood pressure down to an all-time low. He switched from staring at reports on a computer screen to gazing at stars through a telescope. He was happy.

Then he got an email.

It was from a colleague in his former department at AbbVie. The message was rather vague — I have an opportunity I’d like to discuss with you in the neglected disease area — when can we meet? — but intriguing enough for Morton to abandon the window painting for another day, and visit his old stomping grounds to discuss microscopic worms over lunch.

The Tiny Scourge

Over sandwiches with his two former colleagues, he quickly learned that these parasitic creatures cause one of the most devastating diseases seen in the developing world, onchocerciasis, commonly known as river blindness. Endemic in many parts of Sub-Saharan Africa and pockets of Yemen and Latin America, the diseases affects more than 25 million people, most of who live in poverty with little access to health care.

The filarial worms causing onchocerciasis are transmitted by the blackfly into a human host. The worms don’t cause much grief until mating time, at which point the frisky male and female worms produce 700-1,500 microfilaria per day – and the youngsters aren’t as kind to the host as their parents.

The baby worms migrate all over the body and create a toxic response in the host’s immune system that causes “debilitating itching” and skin nodules. They especially like the eyes, and if having worms crawling into your corneas wasn’t horrific enough, their presence can set off a reaction which leads to blindness.

Morton’s first reaction when he saw photos of the filarial worms was how harmless they looked. “They’re really small worms; they’re teeny tiny, and it’s the teeniest tiniest juveniles that actually get to your eyes,” he says.

River blindness falls under the category of neglected tropical diseases, or NTDs. The term is a bit of a misnomer, because it’s not really the diseases that are neglected, but rather the 1 billion people affected by them.

Blind Submission

A few years before Morton’s worm lunch, Thomas (Tom) von Geldern was already enjoying early retirement, cutting down invasive plants and thinking about NTDs.

He’d worked as a medicinal chemist until his department shut down in 2006, at which point he’d opted for “life 2.0.” For von Geldern, this meant flexible consulting work and spending significant amounts of time volunteering for conservation and land-restoration projects in Illinois and Wisconsin, U.S.A., being “one of the guys who goes out to knock down the buckthorn and honeysuckle that don’t belong here, to give the prairie and forests a chance to go back to what they once were like."

Howard Morton spent his short retirement building a deck. Now, he builds molecules.

Tom von Geldern not only donates time to NTD drug discovery, but also to saving the environment.

But no matter how busy he kept himself, he missed the lab.

“It was definitely too early in life to stop doing science,” von Geldern says. “Plus, it takes an enormous amount of time and effort to become even semi-competent at drug discovery, so you hate to completely give that up.”

He’d always had an interest in neglected diseases, and figured the world of not-for-profit drug development might have need for his skill set. After a bit of digging on the internet, he found the Drugs for Neglected Diseases Initiaive (DNDi) website.

“It sounded like DNDi was doing the kind of work I was looking for,” he says. “But I had no contacts there, so I did the world’s stupidest thing: I scrolled down to the bottom of the page where there’s that little button that said ‘contact us.' I wrote a note saying here’s who I am, here’s what I do, and if there’s a way we can work together, please let me know. And then I hit the button and you kind of hear the flushing sound, knowing that your message is going into a hole somewhere.”

Three days later, however, von Geldern got an email with the subject line Small World.

It turned out a former colleague, Shing Chang, was now the head of research for DNDi, and instead of down the drain, von Geldern’s email had made its way to Chang’s inbox. Chang only had two questions for von Geldern: do you have a reasonable amount of time, and are you willing to fly coach?

Von Geldern soon began working with DNDi, getting more heavily involved as years passed. When DNDi and AbbVie began working together on a Bill & Melinda Gates Foundation-funded program seeking treatments for river blindness, von Geldern saw yet another “small world” opportunity: he personally knew Kempf, who was heading up the project (the two had been friends since the 1980s).

A few phone calls, twists of fate and crossing of paths later, von Geldern ended up volunteering his time in an AbbVie laboratory, creating a potential compound to battle filarial worms.

The Worm Project

The Worm Project, as von Geldern affectionately calls it, began at the Liverpool School of Tropical Medicine. Researchers there were honing in on a new strategy to handle the filarial problem that focused on the bacterium Wolbachia, a parasite’s parasite.

“If we kill this symbiotic bacterium, microfilaria can’t grow, female worms can’t reproduce, and adult worms die more quickly. This not only helps the patient, but can block the transmission of the disease.”

Working with the team at Liverpool School, von Geldern and his colleagues began looking at a bunch of antibiotics from the Abbott/AbbVie collection to see if any might fit the profile they were seeking.

And they found one – but there was a problem.

The drug worked well as long as it was injected, but not when taken orally, which was the only realistic way to deliver drugs to the populations affected by river blindness.

“The original molecule has trouble getting across cell membranes … so when you take it orally, it isn’t readily able to get into the bloodstream. For the next year and a half, we tried to figure out if we could change the parts of the molecule that we thought were creating a problem for it getting into tissues and cells,” von Geldern says.

The “we” von Geldern references was mostly just von Geldern, alone in a lab, doing the majority of the discovery chemistry on the promising molecule. It was, he admits, a love/hate relationship.

“To be a drug, a molecule must do many things very well,” he says. “So each time a molecule does what you want it to, you give yourself a little woohoo, and you move on to the next experiment which either gives you another woohoo or a darn. You never want to get too attached to a molecule because one result can make it go away.”

After a few near misses, he found two compounds that seemed to fit the desired profile. “But the better a compound looks, the more questions you need to ask; you need help to test whether the drug is safe, to test whether when you take it orally enough will get into your system.”

He turned to fellow scientists and external partners. It wasn’t a hard ask, however; thanks to Kempf’s talent for getting people engaged, AbbVie scientists have donated more than 60,000 pro-bono hours since 2013 to drug development projects, advisory boards and compound screening to help solve neglected diseases.

“People are excited to do this work, so mostly it’s just asking somebody hey, do you have time to squeeze that in?’” von Geldern says.

Once the initial testing was done, it was clear he had something special on his hands – which meant that he had to pass it to someone else’s hands; hands that could create large enough quantities of the compounds to test their worth.

Those hands belonged to Morton.

Scaling Up

When people learned that Morton would be doing the process chemistry on the river blindness project, there were a lot of quizzical stares.

True, it had been awhile since Morton had done nitty-gritty lab work – he’d ended his career in a managerial role. But looking back on the lunch meeting that resulted in his retirement from retirement, Morton doesn’t see his decision as particularly noteworthy.

“What a great way to give back, with my own hands, to diseases and people that are neglected,” he says.

Shortly after the informational lunch, Morton got to work, taking the compounds von Geldern had created and figuring out how to make them on scale.

Howard Morton hands deep in molecules.

Tom von Geldern in his “natural habitat.”

“I learned about the chemistry, and then thought, how can I make this better?” he says. “What roadblocks do I see, and how can we remove those so when we start making larger amounts we are set to go?”

The creativity he used to jump over those roadblocks is something he credits to years of seeing the "shades of grey" in a field that many of his colleagues feel is black and white.

“In drug discovery, there’s yes or no but there’s also what if. It might be black and white with data, but in terms of developing the compounds, you just don’t know sometimes until you get the result. You’ll have to make decisions, and there’s going to be a lot of grey in that. As scientists, we need to be able to handle it.”

Morton’s keeping this in mind as the compound moves on to the next stage, knowing that all his work could result in disappointment.

“It’s as if your child is finally out there, and the report card’s coming,” Morton says. “It’s scarier than other phases of the process, because most compounds fail in the early stages of the clinical trial process.”

He’s been around long enough to know to take victories where you can find them, though.

“Most compounds never get this far – only 1 percent of them, actually. Which is pretty incredible when you think about it, that we got this from a volunteer effort.”

The Waiting Game

It’s hard to get von Geldern or Morton to take credit for anything. They are adamant that hundreds of hands touched the molecule that could one day change how river blindness is treated.

They also insist that the work they’ve done has been just as rewarding for them as it has been instrumental to the molecule they helped create.

“On a day-to-day basis, the drive is just the science and trying to answer those small questions we have about what we’re trying to make,” von Geldern says.

“But what’s cool about our work is that the things we make really make people’s lives better. It’s hard to imagine a job that’s this much fun to do, fun to practice on the science level, but that still gives you that positive outcome at the end of the day. There aren’t many things that match up with that.”

They do agree that this type of work needs a specific skill set: technical ability, time, dedication and the kind of perspective only experience can bring.

“It’s understanding the big picture, the magnitude of things,” Morton says. “Realizing that it’s not just me, the chemist, on the bench … There’s all these other interactions, things that have to be done and bridges that have to be built to pull this off. And that’s the kind of thing you have to keep your eye on. You’re not in a vacuum. It’s a real team that evolves as the compound develops.”

As for actual retirement, von Geldern doesn’t see it happening for him anytime soon. In fact, he worries that he’ll overstay his welcome.

“There will come a time when they won’t want me in the lab,” he says. “This field continuously evolves, and I’m not as attuned to it as when I was doing it 24/7,365. I can envision that at some point my knowledge and skills will become irrelevant. But for now … these projects are fun; they have the ability to make a difference in people’s lives – so who wouldn’t want to spend time on that?”

Morton wants to stick around to see if this molecule does what it’s meant to do.

“No one has ever used this approach to impact this disease- so the question I want to see answered is, does it work in patients?” Morton says. “I’d love to see yes or no. Because if the answer’s yes, that opens up a whole new way to approach this disease.”

But in terms of lab work, he thinks he’ll step back as soon as this summer, to spend some time with his wife.

Or, maybe not.

“I keep saying I’m going to stop … and then I keep extending it,” he says. “The need is pretty persuasive. The thing is it’s not just one or two people – its millions of people that are at risk for these neglected diseases.”

He stops a minute; then speaks again, more forcefully.

“The fight deserves to be taken. Hopefully we’ll win. And like everything I’ve worked on in my career … there are people waiting.”

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